| What: This app uses pharmacokinetic data to estimate, minute by minute, the contribution made by each of your Parkinson's drugs to your total exogenous levodopa equivalent plasma levels, and graphs the results. |
Instructions: Enter your daily dose data in the green boxes below.
(As it is used here, except where explicitly stated otherwise, the drug name "levodopa" denotes a combined drug levodopa/carbidopa in a 4:1 ratio.) (Where a drug contains levodopa and other active components, input the levodopa dose only.) |
You enter details of your Parkinson's drug regimen:
The program draws a graph showing over a 24 hour period the impact of each drug on a minute-to-minute basis, taking into account the drug's:
(Optional) By inputting estimates of your "on" threshold and your dyskinesia threshold you can read from the graph estimates of the times that you are in these conditions.
(Optional) By inputting longer values of the number of days in treatment you capture the effect of some drugs, those with a long half-life, carrying over their remaining impact to a second and later days. Immediate release levodopa reaches steady state in a day. Some agonists may take five days to reach steady state.
It is usual to measure plasma concentrations in μg/ml. However, in the hope that it is easier to interpret, a different approach is used here. The units of the y-axis are LED mg, scaled such that 100mg denotes the maximum concentration of 100mg of levodopa (taken with carbidopa). This makes it easy to use. For instance, to correct a trough in plasma levels, the additional dose required can be simply read off from the graph.
It is assumed that in an anti-Parkinson's drug regimen:
The idea of pseudo levodopa plasma levels is central to this program. The agonist does not really become levodopa. It's just a matter of convenience that we make this slight of hand. A similar case is made for the inclusion of MAO-B inhibitors in the analysis. They don't literally turn into dopamine, but they make dopamine levels higher than they would otherwise be by lengthening the life of dopamine.
The model used to estimate plasma concentrations is:
1. Each drug has a plasma concentration defined by the following parameters (only 3 of the 4 parameters is are needed, the fourth can be generated from the other 3):
2. Starting at the time that the drug is administered it is assumed that plasma concentrations due to this dose rise linearly until CMAX is reached at TMAX. Thereafter, plasma levels halve every THALF.
3. To deal with non-levodopa based drugs a CMAX value is chosen such that the AUC given by the drug matches that of levodopa multiplied by the LED conversion factor.
The source of the levodopa immediate release pharmacokinetic parameters used here is a paper by Kuoppamaki et al. [5]. These are:
There is a considerable variation in the values of the pharmacokinetic parameters reported in the literature. They are often based on small sample sizes. This leads to inconsistencies: with the LED value implying a different AUC than that reported. For instance, a conversion factor for Stalevo is 1.33, yet using the parameters from [5] in the model gives an AUC 15% higher than that implied by the LED conversion factor.
The conversion factors used are shown in the table below. Where the literature shows large variations in what is thought to be the correct conversion factor to use, a tuple is shown meaning (lowest estimate/highest estimate/average estimate)
| Drug | Conv Factor | CMAX (rel levodopa) | TMAX (min) | THALF (min) | Sources and Notes |
|---|---|---|---|---|---|
| Amantadine | 1 | 0.169 | 126 | 847 | +[14] Choose CMAX to equate AUC. Maximum daily dose is 400mg. |
| Apomorphine (intranasal) | 7.5 | 19.59 | 23 | 31 | +[12] bioavailability of intranasal cf subcutaneous = 45% |
| Apomorphine (subcutaneous) | 10 | 30.62 | 18 | 27 | +[12] |
| Levodopa | 1 | 1 | 60 | 81 | [1]*[5] |
| Levodopa CR | 0.7 | 0.4 | 120 | 137 | * [13] bioavailability 70%, CMAX 60% lower than IR, TMAX approximately 2 hours, THALF chosen to equate AUC |
| Madopar | 1 | 1 | 60 | 81 | *[10] Brand name of levodopa with benserazide |
| Mirapexin | 100 | 19.92 | 120 | 600 | +[11] Max concentrations "between 1 and 3 hours", |
| Neupro Patch | 30 | 3.215 | 0 | 10000 | [15] Brand name of rotigotine patch. Assumed constant levels. CMAX adjusted to equate AUC. |
| Pramipexole | 100 | 19.92 | 120 | 600 | +[11] Max concentrations "between 1 and 3 hours", elimination half life varies from 8 to 12 hours |
| Rasagiline | 100 | 10.72 | 0 | 10000 | [1] Maximum effect found with 1mg. Estimate based on AUC argument and constant effect. |
| Requip | 20 | 5.59 | 90 | 360 | Brand name of ropinirole |
| RequipXL | 20 | 4.34 | 480 | 360 | Inferred from [3]. Brand name of ropinirole CR |
| Ropinirole | 20 | 5.59 | 90 | 360 | [1][2] (16.67,33.3,21.3)[6]+ |
| RopiniroleCR | 20 | 4.34 | 480 | 360 | See RequipXL.[7]+ |
| Rotigotine Patch | 30 | 3.215 | 0 | 10000 | +[15] Constant in steady state. |
| Sinemet | 1 | 1 | 60 | 81 | Brand name of levodopa with carbidopa.* |
| Sinemet CR | 0.7 | 0.4 | 120 | 137 | * [13] brand name Levodopa CR |
| Stalevo | 1.33 | 1.08 | 90 | 117 | [1][2] (1.2,1.33,1.25)*[5] The THALF estimate is derived from [5]. Go to the heading THALF "after the last dose in PD patients". The average of Group I and II is 1.95 hours or 117 minutes as shown. |
Note *: This drug contains multiple components. Input the levodopa dose only.
Note +: TMAX and THALF taken from reference. CMAX is then calculated to give the correct AUC to be consistent with the LED conversion factor (CF).
The conversion factors are clearly rounded which shows that they are estimates.
Different sources give different conversion factors. The range of the estimates for ropinirole, a factor of two, is especially large.
The analysis does not take into account the differences in effectiveness from person to person or the time it takes a drug to start to be absorbed.
Some of the pharmacokinetic data comes from healthy people and some from people with PD; some comes from a single dose trials, and some from steady state doses. Also, there may not have been consistency in regards to food intake, specifically protein, at or around the time of the dose.
Many of the pharmacokinetic trials have had a small sample size.
No attempt is made to take into account endogenous levodopa and dopamine.
The analysis here is based on drug pharmacokinetics, i.e. what the body does to the drug. However, what we are really interested in is drug pharmacodynamics, i.e. what the drug does to the body.
Ron Strong's web site is worth looking at [8]. Angela Wensley has implemented an Excel approach [9] to combine multiple pharmacokinetic curves.
[1] "Levodopa Dose Equivalency: A Systematic Review"
Dr Claire Smith, Birmingham Clinical Trials Unit
8th June 2010
Smith et al.
[2] "Cálculo de unidades de equivalencia de levodopa en enfermedad de Parkinson"
Amin Cervantes-Arriaga1, Mayela Rodríguez-Violante1, Alejandra Villar-Velarde, Teresa Corona
Arch Neurocien (Mex) Vol. 14, No. 2: 116-119; 2009
Range of estimate data
[3] GSK prescribing information for RequipXL
RequipXL prescribing information
[4] Rytary prescribing information
Revised 1/2015
Rytary prescribing information
[5] "Comparison of pharmacokinetic profile of levodopa throughout the day between levodopa/carbidopa/entacapone and levodopa/carbidopa
when administered four or five times daily"
Mikko Kuoppamaki et al.
European Journal of Clinical Pharmacology, May 2009, Volume 65, Issue 5, pp 443-455
Levodopa data
[6] MHRA UK Public Assessment Report, PL 24668/0078-84
Ropinirole data
[7] "Requip XL (ropinirol) - Drug Summary"
GlaxoSmithKline LLC PDR.net
Requip XL data
[9] Angela Wensley, private communication and forum postings
Neurotalk, Parkinson's forum
[10] "Madopar versus Sinemet: A clinical Study on their Effectiveness"
Korten J.J. · Keyser A. · Joosten E.M.G. · Gabreëls F.J.M.
Eur Neurol 1975; 13:65-71
Madopar v Sinemet
[11] "MHRA-UKPAR Pramipexole: PL 29831/0472-5"
March, 2012
MHRA-UKPAR Pramipexole
[12] "Apomorphine pharmacokinetics in parkinsonism after intranasal and subcutaneous application."
Sam E, Jeanjean AP, Maloteaux JM, Verbeke N.
Eur J Drug Metab Pharmacokinetic. 1995
Apomorphine pharmacokinetics
[13] "Sinemet CR and Half Sinemet CR"
emc, 02-Oct-2015
Sinemet CR
[14] "A Randomized, Crossover Study to Evaluate the
Pharmacokinetics of Amantadine and Oseltamivir Administered
Alone and in Combination"
Dennis Morrison et al..
Plos 1, Dec 12, 2007
Amantadine Pharmacokinetics
[15] "Pharmacokinetics, Safety and Tolerability of Rotigotine Transdermal Patch in Healthy Japanese and Caucasian Subjects"
Willi Cawello, Seong R. Kim, Marina Braun, Jan-Peer Elshoff, Junji Ikeda, and Tomoo Funaki
Clin Drug Investig, 2014.
Rotigotine
=============================================